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Therapeutic Drug Monitoring
18
Dawn Merton Boothe
Therapeutic Drug Monitoring
Analysis and Laboratory Availability Artifacts Implementing Therapeutic Drug Monitoring Handling Procedures and Decisions Steady State Loading Dose Number of Samples Timing of Sample Collection Modifying Dose Regimens Therapeutic Monitoring of Selected Drugs
Fixed dosing regimens provided on drug labels are designed to generate plasma drug concentrations (PDCs) within a therapeutic range (Figure 18-1). Plasma drug concentrations are intended to remain above a minimum effective concentration (Cmin) to avoid therapeutic failure while remaining below the maximum concentration (Cmax) and minimizing side effects. Fixed dosing regimens are based on pharmacokinetic studies conducted in a small sample population of normal adults. These regimens, however, are generally administered to unhealthy animals for which drug absorption, distribution, metabolism, or excretion (or a combination of these) have been altered by physiologic factors (e.g., age, gender), pathologic factors (leading to renal or hepatic impairment), or pharmacologic factors (e.g., drug interactions). As a result, PDC may be higher or lower than expected. In these instances, individual monitoring and adjustment of doses using therapeutic drug monitoring (TDM) can optimize drug efficacy and safety. Drugs for which TDM has proven useful in veterinary medicine include selected anticonvulsants (e.g., phenobarbital, primidone, potassium bromide, selected benzodiazepines); 396
Aminoglycosides (Amikacin, Gentamicin) Benzodiazepines (Diazepam, Clorazepate) Bromide Cyclosporine Digoxin Phenobarbital and Primidone Procainamide Theophylline Thyroid Hormones
antimicrobials (e.g., aminoglycosides: gentamicin, amikacin); cardioactive drugs (e.g., digoxin, procainamide, lidocaine); theophylline, thyroid hormones (for thyroid supplementation); and, more recently, cyclosporine (Table 18-1). Indications • TDM may be indicated whenever patients fail to respond appropriately to a drug or when the risk of drug toxicity is great. Specifically, TDM is most useful in six situations when (1) the clinical end point of drug therapy is poorly defined or difficult to detect (e.g., anticonvulsant therapy); (2) the therapeutic index is narrow, indicating little difference exists between effective and toxic PDC (e.g., digoxin, theophylline); (3) marked interindividual pharmacokinetic variability exists, making it difficult to predict PDCs (e.g., phenobarbital); (4) pharmacokinetics are nonlinear, leading to rapid accumulation of toxic concentrations (e.g., phenytoin, phenobarbital [in cats]); (5) drug interactions potentiate toxicity (e.g., enrofloxacin-induced theophylline toxicity, chloramphenicol- or clorazepate-induced phenobarbital toxicity); or (6) when the disease
397
Therapeutic Drug Monitoring Toxic
Log plasma drug concentration
1000
Cmax
Peak
Therapeutic range Trough 100
Cmin
Sub-therapeutic T t1/2
2
4
6
Time (t1/2) FIGURE 18-1. Plasma drug concentrations (PDCs) after multiple administration of a drug with a half-life that is shorter than the dosing interval. In this example, the dose is administered every four half-lives. Because most (94%) of each dose is eliminated before the next dose, PDCs fluctuate markedly. Both toxic and subtherapeutic drug concentrations can occur during a single dosing interval; both peak and trough samples should be collected for such drugs.
is life-threatening, and administration of large doses of drugs is necessary to achieve a prompt response (e.g., epilepsy, bacterial sepsis). Occasionally, TDM is used to identify owner noncompliance as a cause of therapeutic failure or adverse drug reaction, or when overdose may have occured.
ANALYSIS AND LABORATORY AVAILABILITY Generally, PDCs are measured with assays involving specific binding of antibodies to the drug of interest. These antibody-based methods are easily automated and are usually more rapid and cost-effective than chromatographic and spectrophotometric assays, the latter being necessary for a limited number of drugs. With the exception of assay of bromide, which should always be analyzed using the gold chloride method (until the ion-sensitive electrode method is validated), a variety of assay methods can be used to accurately measure PDCs of most drugs. TDM is offered at most veterinary colleges and many diagnostic laboratories in the United States. However, the range of services offered and methods of analysis used vary widely.
Before one submits samples to a particular laboratory, information should be sought regarding procedures for sample handling, delivery, and quality assurance practices. It is imperative that each assay is validated for use in the species of interest and that results generated by the laboratory are accurate and reproducible. When submitting samples to facilities usually serving human patients, one must be cautious not to confuse recommended therapeutic ranges in humans with those in animals (e.g., clorazepate, bromide, procainamide). Among the more critical considerations is the availability of recommendations by a clinical pharmacologist.
ARTIFACTS Assuming proper quality assurance practices are used, false assay results arising from errors related to drug analysis are rare. A notable exception may be for drugs that are metabolized. If the metabolites are active (e.g., clorazepate), the assay should measure all active compounds. If the metabolites are inactive or only weakly active (e.g., cyclosporine), the assay should be specific for the parent compound only (e.g., phenobarbital)
TABLE 18-1. Therapeutic Drug Monitoring Data for Drugs Monitored in Normal, Healthy, Small Animals DRUG
USUAL DOSAGE
INTERVAL (HR)
THERAPEUTIC RANGE*
ELIMINATION HALF-LIFE
TIME TO STEADY STATE
SAMPLE COLLECTION PEAK
SAMPLE COLLECTION TROUGH
Amikacin
15-20 mg/kg
24
2-25 µg/ml1
1-2 hrs
<1 day
1 hr (plastic only)
Two half-lives (3 to 6 hrs)2
10 mg/kg 10 mg/kg 1-2 mg/kg 15-45 mg/kg High: 6.0-8.5 mg/kg Moderate: 3.5-5.5 mg/kg Low: 0.75-3.00 mg/kg
8-12 72
8 hrs 38 hrs <8 hrs 24 days 5.6 hrs
40 hr 8 days 1 day 2-3 months <1 day4
2-4 hrs
BND
2-5 hrs
12-24 12
50-100 µg/ml 50-100 µg/ml 100-200 ng/ml3 1.0-3.5 mg/ml Trough above
2-4 hrs
BND 2 BND BND
12
400 to 600 ng/ml
0.011 mg/kg 0.008 mg/kg
12 12-24
0.9-3.0 ng/ml 0.9-2.0 ng/ml
31.3 hrs 33.5 hrs
7 days 7 days
Toxicity: 2-55 hrs (glass only)
Efficacy: BND5
2-8 mg/kg
12-24
0.5-1.5 µg/ml1
0.9-1.3 hrs
<1 day
1 hr (plastic only)
(cat) Phenobarbital (dog) Primidone (dog)
2-8 mg/kg
12-24
5.0-8.0 µg/ml
Two half-lives (3-6 hrs)2
2 mg/kg
12
20-45 µg/ml
32-75 hrs
14-16 days
4-5 hrs6
BND
11-25 mg/kg
12-24
Based on phenobarbital
6.1 hrs (D)
14-16 days
4-5 hrs6
BND
(cat) Procainamide (dog) Theophylline (dog)
11-20 mg/kg
12-24
15 mg/kg
12
25-50 µg/ml7
2.9 hrs
<1day (15 hrs)
2-4 hrs
BND
7-11 mg/kg or 20 mg/kg slow release 4 mg/kg or 20 mg/kg slow release
8-12; slow release: 12
10-20 µg/ml
5.7 hrs
29 hrs
1-2 hrs8
BND
12-24; slow release: 24
10-20 µg/ml
7.9 hrs
40 hrs
Aspirin (dog) (cat) Benzodiazepines Bromide Cyclosporine
Digoxin (dog) (cat) Gentamicin (dog)
(cat)
12
Thyroid hormones
T3: 4-6 µg/kg (D) 4.4 µg/kg (C) T4: 20 µg/kg (D) 50-100 µg/kg(C)
12-24 12-24 12-24 12-24
0.8-1.5 0.8-1.5 1.5-3.5 1.5-5.0
ng/ml (D)9 ng/ml (C)9 µg/dl (D) µg/dl (C)10
5-6 hrs (D) 12-15 (D)
<24 hrs11
4-5 hrs
BND
11
48-72 hrs
BND, Before next dose; C, cat; D, dog. * Therapeutic ranges are extrapolated from human patients unless noted otherwise. Ranges may also vary with the laboratory findings and specifically with the instrumentation used to assay the drug of interest. Values in this table may be superseded if the values for the instrument have been appropriately validated. Because samples sizes and assay methodologies vary, the specific laboratory that performs the assay should be contacted regarding sample volume, proper collection tubes, need of refrigeration, and other sample handling specifics, as well as “normal” ranges. 1 “Target” peak concentration for aminoglycosides depend on the infecting organism and specifically on the minimum inhibitory concentration (MIC) of the infecting organism. The target peak concentration should be 4 to 10 times the MIC. Trough concentration should be equal or below that recommended to minimize toxicity. 2 For drugs with a very short half-life and at low concentrations, trough sample may no longer have detectable drug. Wait one or two predicted elimination drug halflives between peak and trough sample collections. 3 600 ng/ml listed in humans. Assay should measure all benzodiazepines (parent and active metabolites) relative to dosing interval. If loading, single sample immediately post-load and 3 weeks later. If not loading, single sample at 3 to 4 weeks. For either, collect single sample at 3 months for new baseline. 4 In people; data limited in dogs. Trough of 100 ng/ml may be acceptable for some indications. Concentrations also may vary with assay. Laboratory should be contacted for specific range for their assay. 5 Both peak and trough recommended because of short half-life; single peak acceptable if toxicity is a concern. 6 Peak and trough recommended if seizures are difficult to control. 7 As suggested in Papich MG, Davis LE, Davis CA: Procainamide in the dog: antiarrhythmic plasma concentrations after intravenous administration, J Vet Pharmacol Ther 9:359, 1986. 8 For slow release preparations, one sample may be sufficient. 9 Values for ranges of thyroid hormones reflect an RIA assay. Values are likely to be different for each laboratory. Contact the laboratory, or if doing in house, establish your own normal ranges. Overlap between normal and abnormal is great, regardless of the laboratory and interpretation should be based on clinical signs. 10 Monitoring can occur at any time for cats in whom hyperthyroidism is being managed. 11 Monitoring should not take place until the body has had a chance to physiologically adapt to drug therapy (i.e., 4 to 6 weeks after therapy is implemented).
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Small Animal Clinical Diagnosis by Laboratory Methods
or the therapeutic range of the assay should reflect the metabolites. Thus the therapeutic range of a drug may vary depending on the assay performed. Erroneous PDC data are more likely to be caused by inappropriate sample collection. Serum separator tubes should be avoided because silicon gel in the tubes can bind to and remove drug from the sample, leading to falsely decreased values. Other examples of artifacts caused by collection tubes include binding of aminoglycosides to glass tubes and binding of digoxin to red stoppers. Hemolysis of blood samples and lipemia should be avoided, but their impact is negligible.
concentrations at one half-life, 75% by two half-lives, 87.5% at three half-lives, and so forth (Figure 18-2). Generally, TDM should not be implemented until three to five half-lives have elapsed since initiation of drug therapy. For example, for phenobarbital with a t1/2 of 72 hours, TDM should not be implemented until approximately 15 days after initiation of therapy. If any aspect of the dosing regimen is changed, the same time period (i.e., five half-lives) must elapse for steady-state plasma concentrations to be reestablished. An exception might be made for bromide, for which a sample might be taken at one half-life (i.e., 3 weeks) after a dose is begun to proactively assess a dosing regimen. At one half-life, drug concentrations should approximate the steady-state concentration. Times taken to achieve steady state (as well as other pharmacokinetic and dosing information) are listed in Table 18-1. For drugs with very short t1/2 values compared with the dosing interval (e.g., gentamicin t1/2 = 0.9 to 1.3 hours; dosing interval 12 to 24 hours), steady state is irrelevant, because the drug does not accumulate with repeated dosing. As such, TDM can be initiated immediately (i.e., after the first dose).
IMPLEMENTING THERAPEUTIC DRUG MONITORING Handling Procedures and Decisions In general, serum is monitored; however, most methods can measure drug concentrations in plasma. Cyclosporine should be measured in whole blood. If samples are to be assayed immediately, special handling procedures (e.g., refrigeration, freezing) often are not necessary. Before TDM is conducted, several decisions should be addressed. Three of these are (1) when TDM should be initiated, (2) the number of samples to be collected, and (3) the timing of sample collection. Because of variability among laboratories, the laboratory of submission should be contacted regarding sample submission.
Steady State When therapy is initiated, repeated and regular administration of successive doses may result in accumulation of drug. The greater the half-life compared with the dosing interval, the greater the amount of drug accumulation. Eventually the amount of drug eliminated during each dosing interval equals the amount administered with each dose. At this time, steady state has been reached; peak and trough blood concentrations remain constant as long as dose and dosing interval are not changed. Ideally, TDM and clinical response to therapy should be implemented at steady state to assess maximum response. The time taken for steady state to be reached depends only on the rate of drug elimination (i.e., drug elimination half-life), irrespective of dose or interval. With multiple dosing of drugs that accumulate, PDC reaches 50% of steady-state
Loading Dose When the clinical situation necessitates immediate attainment of therapeutic drug concentrations (e.g., a seizuring patient being treated with bromide), PDC predicted at steady state can be achieved more rapidly by administration of a single loading dose followed by recommended maintenance doses (see Figure 18-2). Loading doses are based on the volume of tissue that dilutes the drug and, for drugs not administered intravenously (IV), the bioavailability of the drug. Despite the fact that steady-state PDCs have been achieved by loading, PDCs are not yet at steady state. PDC achieved after loading may increase or decrease if the maintenance dose is more or less, respectively, than that eliminated during each dosing interval. For bromide in particular, TDM should occur within 1 to 3 days after loading to confirm that targeted concentrations (i.e., predicted steady-state concentrations) have been achieved and again one drug half-life later (i.e., 3 to 4 weeks for bromide) to ensure that the maintenance dose is maintaining the PDC achieved with loading. Although use of a loading dose decreases the time taken for maximum
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Therapeutic Drug Monitoring 10
Log plasma drug concentration
Loading dose
Cmax Peak Trough Cmin
1 87% steady state at 3 t1/2
T t1/2 (accumulation) 1
2
3
Time (t1/2) FIGURE 18-2. Plasma drug concentrations (PDCs) after multiple administration of a drug with a half-life that is longer than the dosing interval. In this example, the dose is given approximately twice every drug half-life. Because little of each dose is eliminated during the dosing interval, little fluctuation occurs and a single sample can be collected for monitoring. To rapidly achieve a pharmacologic effect, a loading dose might be given. A steady-state equilibrium will still occur, however, and PDCs may increase or decrease if the maintenance dose does not maintain what the loading dose achieved.
response to occur (by avoiding slow accumulation to steady state), hazards of adverse reactions are much greater. Thus loading doses are not advised for drugs characterized by a narrow therapeutic index and that tend to cause undesirable adverse reactions (e.g., digoxin).
Number of Samples The relationship between drug half-life and dosing interval (as well as the intent of monitoring) determine the number of samples to be collected. If the dosing interval is longer than drug half-life (e.g., diazepam, most antibiotics), the PDC fluctuates widely during each dosing interval (see Figure 18-1). Assuming that both efficacy and safety are of interest, one should collect two samples to coincide with peak and trough concentrations. For drugs with a long half-life compared with dosing interval, drug concentrations do not change much during each dosing interval, and a single sample generally reflects PDC throughout the dosing interval. For digoxin, collection of both a peak and trough sample is
encouraged because of the narrow therapeutic index of this drug and the marked variability in half-life that can occur in the patient receiving cardiovascular drugs. A single trough sample is often sufficient for phenobarbital. However because elimination halflives of less than 24 hours have been measured, clinicians should collect both a peak and trough sample in patients in which seizure control is difficult.
Timing of Sample Collection Timing for single sample collection depends on the intent of TDM. If efficacy is of concern and only one sampling time is indicated, assessment of trough concentrations is recommended (because these can consistently be compared with subsequent TDM). One can easily determine the trough concentration by collecting the sample immediately before administration of the next dose. Ideally, trough PDC will not drop below recommended Cmin. For drugs with a short halflife compared with the dosing interval (e.g., the aminoglycosides) and for which both
402
Small Animal Clinical Diagnosis by Laboratory Methods
a peak and trough sample will be submitted, collection of a trough sample may result in nondetectable concentrations. Collection of a trough sample at 2 to 3 half-lives after dosing would be more prudent for such drugs. For toxicity, a single peak sample should be determined. Timing of samples used to determine peak concentrations is more difficult to estimate because these samples should only be collected when drug absorption and distribution are complete. In particular, oral absorption of drugs is variable and is influenced by feeding (fasting is generally indicated). Generally, peak PDCs occur 2 to 4 hours after oral administration, although drugs that are absorbed slowly take longer to achieve peak PDC (e.g., 5 hours for phenobarbital). For intramuscular (IM) and subcutaneous (SC) administrations, absorption occurs more rapidly (i.e., 30 to 60 minutes). Absorption times are not relevant to IV-administered drugs, but distribution may take 1 to 2 hours. Thus peak PDCs are generally measured 1 to 2 hours after parenteral drug administration. Peak and trough samples are generally collected during a single dosing interval.
that will achieve a desired target PDC. For example, if the measured peak PDC after administration of 0.011 mg/kg of digoxin to a dog is 0.5 ng/ml and a decision is made to increase the dose to achieve a target peak PDC of 1.5 ng/ml, the new dose can be estimated as follows:
MODIFYING DOSE REGIMENS Precise adjustment of dose regimens requires generation of a pharmacokinetic profile and calculation of pharmacokinetic parameters, such as clearance values and volumes of distribution. If this degree of sophistication is necessary, a specialist in clinical pharmacology should be consulted. A modified profile can be generated from data collected with two (peak and trough) samples. For situations in which precise dose adjustment is not essential and the patient is at steady state, a relatively simple approach is to use the direct proportionality between dose and PDC. For example, if the dose is doubled, the resulting PDC will also be doubled. Conversely, if the dose is halved, the resulting PDC will be halved. The following dose adjustment equation describes this relationship: Old dose × Target PDC New dose = --------------------------------------------Measured PDC With the therapeutic ranges listed in Table 18-1 and PDC results derived from TDM, a new adjusted dose can be calculated
0.011 mg/kg × 1.5 ng/ml 0.5 ng/ml = 0.033 mg/kg
New dose =
Increasing the dose for drugs with a short half-life may result in PDCs that are both too high and too low during a dosing interval. The decision to modify the dose versus interval should take into account client convenience and desired fluctuation in PDC during the dosing interval. The dosing interval also can be changed proportionately, although calculation of elimination half-life provides a more accurate method on which changes in dosing interval can be based. The elimination half-life of a drug can be calculated as t1/2 = 0.693/kel, where kel is the slope of the line drawn between the two TDM points (peak or C1, t2; and trough, C2, t2): kel = ln [C1/C2] divided by t2 − t1. The natural log (ln) must be used because drug elimination is first-order. A clinical pharmacologist can be consulted for assistance in the design of a dosing regimen. The clinician should never base decisions to modify a dosing regimen solely on PDCs and their relationship to the therapeutic range. The therapeutic ranges that accompany TDM results are not the same as “normals” that accompany clinical laboratory tests. A therapeutic range reflects the Cmin and Cmax between which a large percentage (e.g., 95%) of the target population responds to drug therapy. Some animals, however, respond outside the therapeutic range (below Cmin or above Cmax), whereas other animals may become “toxic” within the therapeutic range. Clinical response always must be considered when doses are adjusted. This is particularly important for drugs with effective therapeutic and toxic PDC ranges that overlap (e.g., digoxin, thyroid hormones). Whenever doses are changed, TDM should be continued to confirm that target PDCs have been achieved. When PDCs are within the recommended therapeutic range but the animal fails to respond satisfactorily, minor, “stair step” adjustments in dose are recommended. The size of each increment depends on the
403
Therapeutic Drug Monitoring
therapeutic range and safety of the drug. If a patient’s response to the drug is insufficient, doses are increased proportionately to the desired increase in PDC until either desired response is achieved or maximum limit of the range is reached and risk of adverse effects precludes further increase in dose. For example, phenobarbital (therapeutic range: 15 to 45 µg/ml) should be increased by 5 µg/ml and bromide (therapeutic range: 1.0 to 3.5 mg/ml) by 0.5 mg/ml increments. Doses for each drug are increased by about 25% to achieve the incremental increase. Likewise, if PDCs are close to the maximum of the range (raising concerns that toxicity could result), stepwise decreases can be used to establish the minimum effective concentration necessary to control clinical signs while avoiding toxicity (e.g., anticonvulsant therapy). For each dose change, response should not be evaluated until a new steady state has been reached.
THERAPEUTIC MONITORING OF SELECTED DRUGS Aminoglycosides (Amikacin, Gentamicin) Indications • To monitor aminoglycoside PDCs in life-threatening, serious, or chronic infections caused by susceptible bacteria. Sample Collection • Generally, both Cmax (to verify efficacy) and Cmin (to verify safety) are indicated. Current dosing recommendations are for 24-hour dosing intervals. Ideally, Cmax should be 8 to 10 times the minimum inhibitory concentration of the drug (based on culture and susceptibility data). Cmin concentrations should be less than 2 µg/ml. Because the elimination half-life of the aminoglycosides is short (i.e., 1 to 3 hours), trough concentrations should not be collected just before the next dose because it is unlikely that concentrations will still be detectable. Rather, trough aminoglycoside concentrations should be collected at 4 to 6 hours after peak concentration. Artifacts • Aminoglycosides are bound to glass. Samples intended for TDM should not be collected in glass tubes or should be immediately transferred upon collection to plastic tubes. Dosing Modification • Doses can be proportionately increased or decreased based on Cmax. Intervals should be prolonged in
increments of one drug half-life if Cmin is above recommended trough concentration (see Table 18-1).
Benzodiazepines (Diazepam, Clorazepate) Indications • To make sure PDCs do not drop below Cmin in patients receiving the drug for long-term seizure control. Diazepam is generally measured in cats and clorazepate in dogs. Because each is metabolized to active metabolites, both parent drug and metabolites are monitored. Sample Collection • The elimination half-life of the benzodiazepines is short, and PDCs fluctuate dramatically during an 8-hour or 12-hour dosing interval. Two samples are recommended (see Table 18-1). Dosing Modification • The interval should be decreased if PDCs markedly fluctuate during the dosing interval. The dose should be changed proportionately as indicated by PDCs. Both the dose and interval may be modified simultaneously.
Bromide Indications • Any epileptic patient receiving the drug. Regardless of the salt used, bromide is the active ingredient measured. Sample Collection • The half-life of bromide is very long compared with the dosing interval; hence, single samples are indicated for TDM. Trough concentrations are recommended, although any time during the dosing interval is acceptable. Concentrations should be measured at baseline steady state, at 3- to 6-month intervals, and any time the animal has a seizure. Proactive monitoring should occur after a loading dose and at 1 month post-load. If a loading dose is not administered, monitoring should occur 1 month into therapy. A clinical pharmacologist is strongly recommended for consultation when monitoring bromide. Artifacts • Only one method using gold chloride has been validated for monitoring bromide in serum. As mentioned previously, until the ion-sensitive electrode method is validated in serum, such methods should not be used for bromide analysis. Bromide can cause chloride concentrations to be artifactually increased.
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Small Animal Clinical Diagnosis by Laboratory Methods
Cyclosporine
Artifacts • Red stoppers on collection tubes may bind drug, decreasing concentrations.
Indications • In patients undergoing organ transplantation or in selected immunemediated diseases. The drug has not been extensively used in dogs or cats and can cause toxicity. However, toxic concentrations have not been established in animals. Sample Collection • Because the half-life is sufficiently short, both peak and trough concentrations should be collected (see Table 18-1). If a single sample is collected, a trough sample is indicated. Because the drug distributes to red blood cells (RBCs), whole blood generally should be collected. Dosing Modification • Ideally, both dose and interval should be altered as necessary. If single samples are collected, the dose should be proportionally changed. The therapeutic range is generally based on trough samples and varies with the methodology and the disease being treated.
Digoxin Indications • In patients suspected of digoxin toxicity or in patients with inadequate response. Sample Collection • Both a peak and trough sample are necessary to design the safest and most effective dosing regimen, particularly in patients with an inadequate response or those in which disposition of digoxin is likely to be abnormal because of changes in renal and hepatic function induced by either disease or drug therapy. If toxicity is of concern, a single peak sample may be sufficient. Absorption and distribution of digoxin can vary with product used and the patient, and it can take up to 8 hours. Peak concentrations at 3 to 5 hours are recommended (see Table 18-1). The half-life of digoxin also varies, being as short as 12 hours in some animals despite a 36-hour half-life reported in normal animals. Thus, both a peak and trough sample are recommended. If a single sample is to be collected to evaluate efficacy, a trough sample should be collected. Because cardiac disease can cause marked disposition changes, TDM should be implemented before and after response to afterload therapy, diuretic therapy, or both because disposition is likely to change as the disease responds to therapy.
Dosing Modification • If a single sample has been collected, the dose of digoxin should be changed proportionately. If both peak and trough samples are collected, a pharmacokinetic profile (see earlier) should be generated for the patient and an interval appropriate and convenient should be established along with a new dose.
Phenobarbital and Primidone Indications • Any animal receiving either of these drugs for seizure control. Primidone is converted to phenobarbital, which is measured rather than primidone. The disposition of both drugs varies markedly among animals. In addition, both drugs cause induction of drug-metabolizing enzymes, leading to greater variability. Finally, side effects (i.e., grogginess, hepatotoxicity) of the drug are of sufficient concern that samples should be monitored for safety. Sample Collection • The half-life of phenobarbital can be short enough to necessitate both peak and trough samples, or it can be long enough to allow only a trough sample collection. Both peak and trough samples are recommended at baseline and, in anticipation of induction, 1 to 3 months later (see Table 18-1). If the patient remains seizurefree, a single trough sample is sufficient at 6-month intervals. However, if the patient has a “breakthrough” seizure, both peak and trough samples are recommended.
Procainamide Indications • Although not routine, procainamide could be monitored in patients responding inadequately to long-term control of cardiac arrhythmias. NOTE: Efficacy of procainamide in people reflects an active metabolite that is minimally formed in dogs. Recommended concentrations reflect both procainamide and its acetylated metabolite. Sample Collection • Because the halflife of procainamide is sufficiently short and the potential of adverse drug interactions sufficiently great, both peak and trough
405
Therapeutic Drug Monitoring
samples should be collected (see Table 18-1). A single trough sample can also be used to verify efficacy.
Theophylline Indications • In patients receiving the drug as a bronchodilator that have not experienced sufficient response and those suspected of reacting adversely to theophylline. Sample Collection • The half-life of regular theophylline is short enough that it is best to collect both peak and trough samples (see Table 18-1). For efficacy, a single trough sample is acceptable. For safety (i.e., detection of adverse reactions), a single peak sample can be collected. For slow-release preparations, absorption is slow enough that a single trough sample is sufficient. Dosing Modification • The dose of theophylline can be changed proportionately. Intervals can be modified if both peak and trough data are available.
Thyroid Hormones Indications • In any animal receiving thyroid supplementation (usually dogs) or animals with hyperthyroidism that are being medically managed (usually cats). Because thyroxine (T4) is the circulating hormone of interest (T3 being located primarily intracellularly), it is generally the hormone measured.
The majority of the hormone is bound to proteins and thus is pharmacologically inactive; therefore, free T4 (fT4) may be the preferred hormone to be tested. Equilibrium dialysis is the most accurate method to measure fT4. Sample Collection • Although concentrations of hormones may achieve steady state rapidly, the body may not equilibrate immediately. Physiologic equilibrium to the thyroid hormones may take 4 to 6 weeks, and monitoring should not take place until equilibrium is likely to have occurred (see Table 18-1). Likewise, response to drugs intended to control hyperthyroidism may take 3 to 4 weeks. Analysis • Methods that have been validated in the species of interest are preferred. Dosing Modification • Doses should be altered proportionately.
References Neff-Davis CA: Therapeutic drug monitoring in veterinary medicine, Vet Clin North Am Small Anim Pract 18(6): 1287, 1988. Pippenger CF, Massoud N: Therapeutic drug monitoring. In Benet LZ et al, editors: Pharmacokinetic basis for drug therapy, New York, 1984, Raven Press. Price CP: Analytical techniques for therapeutic drug monitoring, Clin Biochem 17:52, 1984. Therapeutic drug monitoring, clinical guide, Abbott Laboratories, Diagnostic Division, Dallas, TX, 1984, Abbott Laboratories. Wilson RC: Therapeutic drug monitoring, Auburn Vet 42(3):20, 1987.
Dawn Merton Boothe
Therapeutic Drug Monitoring
Analysis and Laboratory Availability Artifacts Implementing Therapeutic Drug Monitoring Handling Procedures and Decisions Steady State Loading Dose Number of Samples Timing of Sample Collection Modifying Dose Regimens Therapeutic Monitoring of Selected Drugs
Fixed dosing regimens provided on drug labels are designed to generate plasma drug concentrations (PDCs) within a therapeutic range (Figure 18-1). Plasma drug concentrations are intended to remain above a minimum effective concentration (Cmin) to avoid therapeutic failure while remaining below the maximum concentration (Cmax) and minimizing side effects. Fixed dosing regimens are based on pharmacokinetic studies conducted in a small sample population of normal adults. These regimens, however, are generally administered to unhealthy animals for which drug absorption, distribution, metabolism, or excretion (or a combination of these) have been altered by physiologic factors (e.g., age, gender), pathologic factors (leading to renal or hepatic impairment), or pharmacologic factors (e.g., drug interactions). As a result, PDC may be higher or lower than expected. In these instances, individual monitoring and adjustment of doses using therapeutic drug monitoring (TDM) can optimize drug efficacy and safety. Drugs for which TDM has proven useful in veterinary medicine include selected anticonvulsants (e.g., phenobarbital, primidone, potassium bromide, selected benzodiazepines); 396
Aminoglycosides (Amikacin, Gentamicin) Benzodiazepines (Diazepam, Clorazepate) Bromide Cyclosporine Digoxin Phenobarbital and Primidone Procainamide Theophylline Thyroid Hormones
antimicrobials (e.g., aminoglycosides: gentamicin, amikacin); cardioactive drugs (e.g., digoxin, procainamide, lidocaine); theophylline, thyroid hormones (for thyroid supplementation); and, more recently, cyclosporine (Table 18-1). Indications • TDM may be indicated whenever patients fail to respond appropriately to a drug or when the risk of drug toxicity is great. Specifically, TDM is most useful in six situations when (1) the clinical end point of drug therapy is poorly defined or difficult to detect (e.g., anticonvulsant therapy); (2) the therapeutic index is narrow, indicating little difference exists between effective and toxic PDC (e.g., digoxin, theophylline); (3) marked interindividual pharmacokinetic variability exists, making it difficult to predict PDCs (e.g., phenobarbital); (4) pharmacokinetics are nonlinear, leading to rapid accumulation of toxic concentrations (e.g., phenytoin, phenobarbital [in cats]); (5) drug interactions potentiate toxicity (e.g., enrofloxacin-induced theophylline toxicity, chloramphenicol- or clorazepate-induced phenobarbital toxicity); or (6) when the disease
397
Therapeutic Drug Monitoring Toxic
Log plasma drug concentration
1000
Cmax
Peak
Therapeutic range Trough 100
Cmin
Sub-therapeutic T t1/2
2
4
6
Time (t1/2) FIGURE 18-1. Plasma drug concentrations (PDCs) after multiple administration of a drug with a half-life that is shorter than the dosing interval. In this example, the dose is administered every four half-lives. Because most (94%) of each dose is eliminated before the next dose, PDCs fluctuate markedly. Both toxic and subtherapeutic drug concentrations can occur during a single dosing interval; both peak and trough samples should be collected for such drugs.
is life-threatening, and administration of large doses of drugs is necessary to achieve a prompt response (e.g., epilepsy, bacterial sepsis). Occasionally, TDM is used to identify owner noncompliance as a cause of therapeutic failure or adverse drug reaction, or when overdose may have occured.
ANALYSIS AND LABORATORY AVAILABILITY Generally, PDCs are measured with assays involving specific binding of antibodies to the drug of interest. These antibody-based methods are easily automated and are usually more rapid and cost-effective than chromatographic and spectrophotometric assays, the latter being necessary for a limited number of drugs. With the exception of assay of bromide, which should always be analyzed using the gold chloride method (until the ion-sensitive electrode method is validated), a variety of assay methods can be used to accurately measure PDCs of most drugs. TDM is offered at most veterinary colleges and many diagnostic laboratories in the United States. However, the range of services offered and methods of analysis used vary widely.
Before one submits samples to a particular laboratory, information should be sought regarding procedures for sample handling, delivery, and quality assurance practices. It is imperative that each assay is validated for use in the species of interest and that results generated by the laboratory are accurate and reproducible. When submitting samples to facilities usually serving human patients, one must be cautious not to confuse recommended therapeutic ranges in humans with those in animals (e.g., clorazepate, bromide, procainamide). Among the more critical considerations is the availability of recommendations by a clinical pharmacologist.
ARTIFACTS Assuming proper quality assurance practices are used, false assay results arising from errors related to drug analysis are rare. A notable exception may be for drugs that are metabolized. If the metabolites are active (e.g., clorazepate), the assay should measure all active compounds. If the metabolites are inactive or only weakly active (e.g., cyclosporine), the assay should be specific for the parent compound only (e.g., phenobarbital)
TABLE 18-1. Therapeutic Drug Monitoring Data for Drugs Monitored in Normal, Healthy, Small Animals DRUG
USUAL DOSAGE
INTERVAL (HR)
THERAPEUTIC RANGE*
ELIMINATION HALF-LIFE
TIME TO STEADY STATE
SAMPLE COLLECTION PEAK
SAMPLE COLLECTION TROUGH
Amikacin
15-20 mg/kg
24
2-25 µg/ml1
1-2 hrs
<1 day
1 hr (plastic only)
Two half-lives (3 to 6 hrs)2
10 mg/kg 10 mg/kg 1-2 mg/kg 15-45 mg/kg High: 6.0-8.5 mg/kg Moderate: 3.5-5.5 mg/kg Low: 0.75-3.00 mg/kg
8-12 72
8 hrs 38 hrs <8 hrs 24 days 5.6 hrs
40 hr 8 days 1 day 2-3 months <1 day4
2-4 hrs
BND
2-5 hrs
12-24 12
50-100 µg/ml 50-100 µg/ml 100-200 ng/ml3 1.0-3.5 mg/ml Trough above
2-4 hrs
BND 2 BND BND
12
400 to 600 ng/ml
0.011 mg/kg 0.008 mg/kg
12 12-24
0.9-3.0 ng/ml 0.9-2.0 ng/ml
31.3 hrs 33.5 hrs
7 days 7 days
Toxicity: 2-55 hrs (glass only)
Efficacy: BND5
2-8 mg/kg
12-24
0.5-1.5 µg/ml1
0.9-1.3 hrs
<1 day
1 hr (plastic only)
(cat) Phenobarbital (dog) Primidone (dog)
2-8 mg/kg
12-24
5.0-8.0 µg/ml
Two half-lives (3-6 hrs)2
2 mg/kg
12
20-45 µg/ml
32-75 hrs
14-16 days
4-5 hrs6
BND
11-25 mg/kg
12-24
Based on phenobarbital
6.1 hrs (D)
14-16 days
4-5 hrs6
BND
(cat) Procainamide (dog) Theophylline (dog)
11-20 mg/kg
12-24
15 mg/kg
12
25-50 µg/ml7
2.9 hrs
<1day (15 hrs)
2-4 hrs
BND
7-11 mg/kg or 20 mg/kg slow release 4 mg/kg or 20 mg/kg slow release
8-12; slow release: 12
10-20 µg/ml
5.7 hrs
29 hrs
1-2 hrs8
BND
12-24; slow release: 24
10-20 µg/ml
7.9 hrs
40 hrs
Aspirin (dog) (cat) Benzodiazepines Bromide Cyclosporine
Digoxin (dog) (cat) Gentamicin (dog)
(cat)
12
Thyroid hormones
T3: 4-6 µg/kg (D) 4.4 µg/kg (C) T4: 20 µg/kg (D) 50-100 µg/kg(C)
12-24 12-24 12-24 12-24
0.8-1.5 0.8-1.5 1.5-3.5 1.5-5.0
ng/ml (D)9 ng/ml (C)9 µg/dl (D) µg/dl (C)10
5-6 hrs (D) 12-15 (D)
<24 hrs11
4-5 hrs
BND
11
48-72 hrs
BND, Before next dose; C, cat; D, dog. * Therapeutic ranges are extrapolated from human patients unless noted otherwise. Ranges may also vary with the laboratory findings and specifically with the instrumentation used to assay the drug of interest. Values in this table may be superseded if the values for the instrument have been appropriately validated. Because samples sizes and assay methodologies vary, the specific laboratory that performs the assay should be contacted regarding sample volume, proper collection tubes, need of refrigeration, and other sample handling specifics, as well as “normal” ranges. 1 “Target” peak concentration for aminoglycosides depend on the infecting organism and specifically on the minimum inhibitory concentration (MIC) of the infecting organism. The target peak concentration should be 4 to 10 times the MIC. Trough concentration should be equal or below that recommended to minimize toxicity. 2 For drugs with a very short half-life and at low concentrations, trough sample may no longer have detectable drug. Wait one or two predicted elimination drug halflives between peak and trough sample collections. 3 600 ng/ml listed in humans. Assay should measure all benzodiazepines (parent and active metabolites) relative to dosing interval. If loading, single sample immediately post-load and 3 weeks later. If not loading, single sample at 3 to 4 weeks. For either, collect single sample at 3 months for new baseline. 4 In people; data limited in dogs. Trough of 100 ng/ml may be acceptable for some indications. Concentrations also may vary with assay. Laboratory should be contacted for specific range for their assay. 5 Both peak and trough recommended because of short half-life; single peak acceptable if toxicity is a concern. 6 Peak and trough recommended if seizures are difficult to control. 7 As suggested in Papich MG, Davis LE, Davis CA: Procainamide in the dog: antiarrhythmic plasma concentrations after intravenous administration, J Vet Pharmacol Ther 9:359, 1986. 8 For slow release preparations, one sample may be sufficient. 9 Values for ranges of thyroid hormones reflect an RIA assay. Values are likely to be different for each laboratory. Contact the laboratory, or if doing in house, establish your own normal ranges. Overlap between normal and abnormal is great, regardless of the laboratory and interpretation should be based on clinical signs. 10 Monitoring can occur at any time for cats in whom hyperthyroidism is being managed. 11 Monitoring should not take place until the body has had a chance to physiologically adapt to drug therapy (i.e., 4 to 6 weeks after therapy is implemented).
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Small Animal Clinical Diagnosis by Laboratory Methods
or the therapeutic range of the assay should reflect the metabolites. Thus the therapeutic range of a drug may vary depending on the assay performed. Erroneous PDC data are more likely to be caused by inappropriate sample collection. Serum separator tubes should be avoided because silicon gel in the tubes can bind to and remove drug from the sample, leading to falsely decreased values. Other examples of artifacts caused by collection tubes include binding of aminoglycosides to glass tubes and binding of digoxin to red stoppers. Hemolysis of blood samples and lipemia should be avoided, but their impact is negligible.
concentrations at one half-life, 75% by two half-lives, 87.5% at three half-lives, and so forth (Figure 18-2). Generally, TDM should not be implemented until three to five half-lives have elapsed since initiation of drug therapy. For example, for phenobarbital with a t1/2 of 72 hours, TDM should not be implemented until approximately 15 days after initiation of therapy. If any aspect of the dosing regimen is changed, the same time period (i.e., five half-lives) must elapse for steady-state plasma concentrations to be reestablished. An exception might be made for bromide, for which a sample might be taken at one half-life (i.e., 3 weeks) after a dose is begun to proactively assess a dosing regimen. At one half-life, drug concentrations should approximate the steady-state concentration. Times taken to achieve steady state (as well as other pharmacokinetic and dosing information) are listed in Table 18-1. For drugs with very short t1/2 values compared with the dosing interval (e.g., gentamicin t1/2 = 0.9 to 1.3 hours; dosing interval 12 to 24 hours), steady state is irrelevant, because the drug does not accumulate with repeated dosing. As such, TDM can be initiated immediately (i.e., after the first dose).
IMPLEMENTING THERAPEUTIC DRUG MONITORING Handling Procedures and Decisions In general, serum is monitored; however, most methods can measure drug concentrations in plasma. Cyclosporine should be measured in whole blood. If samples are to be assayed immediately, special handling procedures (e.g., refrigeration, freezing) often are not necessary. Before TDM is conducted, several decisions should be addressed. Three of these are (1) when TDM should be initiated, (2) the number of samples to be collected, and (3) the timing of sample collection. Because of variability among laboratories, the laboratory of submission should be contacted regarding sample submission.
Steady State When therapy is initiated, repeated and regular administration of successive doses may result in accumulation of drug. The greater the half-life compared with the dosing interval, the greater the amount of drug accumulation. Eventually the amount of drug eliminated during each dosing interval equals the amount administered with each dose. At this time, steady state has been reached; peak and trough blood concentrations remain constant as long as dose and dosing interval are not changed. Ideally, TDM and clinical response to therapy should be implemented at steady state to assess maximum response. The time taken for steady state to be reached depends only on the rate of drug elimination (i.e., drug elimination half-life), irrespective of dose or interval. With multiple dosing of drugs that accumulate, PDC reaches 50% of steady-state
Loading Dose When the clinical situation necessitates immediate attainment of therapeutic drug concentrations (e.g., a seizuring patient being treated with bromide), PDC predicted at steady state can be achieved more rapidly by administration of a single loading dose followed by recommended maintenance doses (see Figure 18-2). Loading doses are based on the volume of tissue that dilutes the drug and, for drugs not administered intravenously (IV), the bioavailability of the drug. Despite the fact that steady-state PDCs have been achieved by loading, PDCs are not yet at steady state. PDC achieved after loading may increase or decrease if the maintenance dose is more or less, respectively, than that eliminated during each dosing interval. For bromide in particular, TDM should occur within 1 to 3 days after loading to confirm that targeted concentrations (i.e., predicted steady-state concentrations) have been achieved and again one drug half-life later (i.e., 3 to 4 weeks for bromide) to ensure that the maintenance dose is maintaining the PDC achieved with loading. Although use of a loading dose decreases the time taken for maximum
401
Therapeutic Drug Monitoring 10
Log plasma drug concentration
Loading dose
Cmax Peak Trough Cmin
1 87% steady state at 3 t1/2
T t1/2 (accumulation) 1
2
3
Time (t1/2) FIGURE 18-2. Plasma drug concentrations (PDCs) after multiple administration of a drug with a half-life that is longer than the dosing interval. In this example, the dose is given approximately twice every drug half-life. Because little of each dose is eliminated during the dosing interval, little fluctuation occurs and a single sample can be collected for monitoring. To rapidly achieve a pharmacologic effect, a loading dose might be given. A steady-state equilibrium will still occur, however, and PDCs may increase or decrease if the maintenance dose does not maintain what the loading dose achieved.
response to occur (by avoiding slow accumulation to steady state), hazards of adverse reactions are much greater. Thus loading doses are not advised for drugs characterized by a narrow therapeutic index and that tend to cause undesirable adverse reactions (e.g., digoxin).
Number of Samples The relationship between drug half-life and dosing interval (as well as the intent of monitoring) determine the number of samples to be collected. If the dosing interval is longer than drug half-life (e.g., diazepam, most antibiotics), the PDC fluctuates widely during each dosing interval (see Figure 18-1). Assuming that both efficacy and safety are of interest, one should collect two samples to coincide with peak and trough concentrations. For drugs with a long half-life compared with dosing interval, drug concentrations do not change much during each dosing interval, and a single sample generally reflects PDC throughout the dosing interval. For digoxin, collection of both a peak and trough sample is
encouraged because of the narrow therapeutic index of this drug and the marked variability in half-life that can occur in the patient receiving cardiovascular drugs. A single trough sample is often sufficient for phenobarbital. However because elimination halflives of less than 24 hours have been measured, clinicians should collect both a peak and trough sample in patients in which seizure control is difficult.
Timing of Sample Collection Timing for single sample collection depends on the intent of TDM. If efficacy is of concern and only one sampling time is indicated, assessment of trough concentrations is recommended (because these can consistently be compared with subsequent TDM). One can easily determine the trough concentration by collecting the sample immediately before administration of the next dose. Ideally, trough PDC will not drop below recommended Cmin. For drugs with a short halflife compared with the dosing interval (e.g., the aminoglycosides) and for which both
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Small Animal Clinical Diagnosis by Laboratory Methods
a peak and trough sample will be submitted, collection of a trough sample may result in nondetectable concentrations. Collection of a trough sample at 2 to 3 half-lives after dosing would be more prudent for such drugs. For toxicity, a single peak sample should be determined. Timing of samples used to determine peak concentrations is more difficult to estimate because these samples should only be collected when drug absorption and distribution are complete. In particular, oral absorption of drugs is variable and is influenced by feeding (fasting is generally indicated). Generally, peak PDCs occur 2 to 4 hours after oral administration, although drugs that are absorbed slowly take longer to achieve peak PDC (e.g., 5 hours for phenobarbital). For intramuscular (IM) and subcutaneous (SC) administrations, absorption occurs more rapidly (i.e., 30 to 60 minutes). Absorption times are not relevant to IV-administered drugs, but distribution may take 1 to 2 hours. Thus peak PDCs are generally measured 1 to 2 hours after parenteral drug administration. Peak and trough samples are generally collected during a single dosing interval.
that will achieve a desired target PDC. For example, if the measured peak PDC after administration of 0.011 mg/kg of digoxin to a dog is 0.5 ng/ml and a decision is made to increase the dose to achieve a target peak PDC of 1.5 ng/ml, the new dose can be estimated as follows:
MODIFYING DOSE REGIMENS Precise adjustment of dose regimens requires generation of a pharmacokinetic profile and calculation of pharmacokinetic parameters, such as clearance values and volumes of distribution. If this degree of sophistication is necessary, a specialist in clinical pharmacology should be consulted. A modified profile can be generated from data collected with two (peak and trough) samples. For situations in which precise dose adjustment is not essential and the patient is at steady state, a relatively simple approach is to use the direct proportionality between dose and PDC. For example, if the dose is doubled, the resulting PDC will also be doubled. Conversely, if the dose is halved, the resulting PDC will be halved. The following dose adjustment equation describes this relationship: Old dose × Target PDC New dose = --------------------------------------------Measured PDC With the therapeutic ranges listed in Table 18-1 and PDC results derived from TDM, a new adjusted dose can be calculated
0.011 mg/kg × 1.5 ng/ml 0.5 ng/ml = 0.033 mg/kg
New dose =
Increasing the dose for drugs with a short half-life may result in PDCs that are both too high and too low during a dosing interval. The decision to modify the dose versus interval should take into account client convenience and desired fluctuation in PDC during the dosing interval. The dosing interval also can be changed proportionately, although calculation of elimination half-life provides a more accurate method on which changes in dosing interval can be based. The elimination half-life of a drug can be calculated as t1/2 = 0.693/kel, where kel is the slope of the line drawn between the two TDM points (peak or C1, t2; and trough, C2, t2): kel = ln [C1/C2] divided by t2 − t1. The natural log (ln) must be used because drug elimination is first-order. A clinical pharmacologist can be consulted for assistance in the design of a dosing regimen. The clinician should never base decisions to modify a dosing regimen solely on PDCs and their relationship to the therapeutic range. The therapeutic ranges that accompany TDM results are not the same as “normals” that accompany clinical laboratory tests. A therapeutic range reflects the Cmin and Cmax between which a large percentage (e.g., 95%) of the target population responds to drug therapy. Some animals, however, respond outside the therapeutic range (below Cmin or above Cmax), whereas other animals may become “toxic” within the therapeutic range. Clinical response always must be considered when doses are adjusted. This is particularly important for drugs with effective therapeutic and toxic PDC ranges that overlap (e.g., digoxin, thyroid hormones). Whenever doses are changed, TDM should be continued to confirm that target PDCs have been achieved. When PDCs are within the recommended therapeutic range but the animal fails to respond satisfactorily, minor, “stair step” adjustments in dose are recommended. The size of each increment depends on the
403
Therapeutic Drug Monitoring
therapeutic range and safety of the drug. If a patient’s response to the drug is insufficient, doses are increased proportionately to the desired increase in PDC until either desired response is achieved or maximum limit of the range is reached and risk of adverse effects precludes further increase in dose. For example, phenobarbital (therapeutic range: 15 to 45 µg/ml) should be increased by 5 µg/ml and bromide (therapeutic range: 1.0 to 3.5 mg/ml) by 0.5 mg/ml increments. Doses for each drug are increased by about 25% to achieve the incremental increase. Likewise, if PDCs are close to the maximum of the range (raising concerns that toxicity could result), stepwise decreases can be used to establish the minimum effective concentration necessary to control clinical signs while avoiding toxicity (e.g., anticonvulsant therapy). For each dose change, response should not be evaluated until a new steady state has been reached.
THERAPEUTIC MONITORING OF SELECTED DRUGS Aminoglycosides (Amikacin, Gentamicin) Indications • To monitor aminoglycoside PDCs in life-threatening, serious, or chronic infections caused by susceptible bacteria. Sample Collection • Generally, both Cmax (to verify efficacy) and Cmin (to verify safety) are indicated. Current dosing recommendations are for 24-hour dosing intervals. Ideally, Cmax should be 8 to 10 times the minimum inhibitory concentration of the drug (based on culture and susceptibility data). Cmin concentrations should be less than 2 µg/ml. Because the elimination half-life of the aminoglycosides is short (i.e., 1 to 3 hours), trough concentrations should not be collected just before the next dose because it is unlikely that concentrations will still be detectable. Rather, trough aminoglycoside concentrations should be collected at 4 to 6 hours after peak concentration. Artifacts • Aminoglycosides are bound to glass. Samples intended for TDM should not be collected in glass tubes or should be immediately transferred upon collection to plastic tubes. Dosing Modification • Doses can be proportionately increased or decreased based on Cmax. Intervals should be prolonged in
increments of one drug half-life if Cmin is above recommended trough concentration (see Table 18-1).
Benzodiazepines (Diazepam, Clorazepate) Indications • To make sure PDCs do not drop below Cmin in patients receiving the drug for long-term seizure control. Diazepam is generally measured in cats and clorazepate in dogs. Because each is metabolized to active metabolites, both parent drug and metabolites are monitored. Sample Collection • The elimination half-life of the benzodiazepines is short, and PDCs fluctuate dramatically during an 8-hour or 12-hour dosing interval. Two samples are recommended (see Table 18-1). Dosing Modification • The interval should be decreased if PDCs markedly fluctuate during the dosing interval. The dose should be changed proportionately as indicated by PDCs. Both the dose and interval may be modified simultaneously.
Bromide Indications • Any epileptic patient receiving the drug. Regardless of the salt used, bromide is the active ingredient measured. Sample Collection • The half-life of bromide is very long compared with the dosing interval; hence, single samples are indicated for TDM. Trough concentrations are recommended, although any time during the dosing interval is acceptable. Concentrations should be measured at baseline steady state, at 3- to 6-month intervals, and any time the animal has a seizure. Proactive monitoring should occur after a loading dose and at 1 month post-load. If a loading dose is not administered, monitoring should occur 1 month into therapy. A clinical pharmacologist is strongly recommended for consultation when monitoring bromide. Artifacts • Only one method using gold chloride has been validated for monitoring bromide in serum. As mentioned previously, until the ion-sensitive electrode method is validated in serum, such methods should not be used for bromide analysis. Bromide can cause chloride concentrations to be artifactually increased.
404
Small Animal Clinical Diagnosis by Laboratory Methods
Cyclosporine
Artifacts • Red stoppers on collection tubes may bind drug, decreasing concentrations.
Indications • In patients undergoing organ transplantation or in selected immunemediated diseases. The drug has not been extensively used in dogs or cats and can cause toxicity. However, toxic concentrations have not been established in animals. Sample Collection • Because the half-life is sufficiently short, both peak and trough concentrations should be collected (see Table 18-1). If a single sample is collected, a trough sample is indicated. Because the drug distributes to red blood cells (RBCs), whole blood generally should be collected. Dosing Modification • Ideally, both dose and interval should be altered as necessary. If single samples are collected, the dose should be proportionally changed. The therapeutic range is generally based on trough samples and varies with the methodology and the disease being treated.
Digoxin Indications • In patients suspected of digoxin toxicity or in patients with inadequate response. Sample Collection • Both a peak and trough sample are necessary to design the safest and most effective dosing regimen, particularly in patients with an inadequate response or those in which disposition of digoxin is likely to be abnormal because of changes in renal and hepatic function induced by either disease or drug therapy. If toxicity is of concern, a single peak sample may be sufficient. Absorption and distribution of digoxin can vary with product used and the patient, and it can take up to 8 hours. Peak concentrations at 3 to 5 hours are recommended (see Table 18-1). The half-life of digoxin also varies, being as short as 12 hours in some animals despite a 36-hour half-life reported in normal animals. Thus, both a peak and trough sample are recommended. If a single sample is to be collected to evaluate efficacy, a trough sample should be collected. Because cardiac disease can cause marked disposition changes, TDM should be implemented before and after response to afterload therapy, diuretic therapy, or both because disposition is likely to change as the disease responds to therapy.
Dosing Modification • If a single sample has been collected, the dose of digoxin should be changed proportionately. If both peak and trough samples are collected, a pharmacokinetic profile (see earlier) should be generated for the patient and an interval appropriate and convenient should be established along with a new dose.
Phenobarbital and Primidone Indications • Any animal receiving either of these drugs for seizure control. Primidone is converted to phenobarbital, which is measured rather than primidone. The disposition of both drugs varies markedly among animals. In addition, both drugs cause induction of drug-metabolizing enzymes, leading to greater variability. Finally, side effects (i.e., grogginess, hepatotoxicity) of the drug are of sufficient concern that samples should be monitored for safety. Sample Collection • The half-life of phenobarbital can be short enough to necessitate both peak and trough samples, or it can be long enough to allow only a trough sample collection. Both peak and trough samples are recommended at baseline and, in anticipation of induction, 1 to 3 months later (see Table 18-1). If the patient remains seizurefree, a single trough sample is sufficient at 6-month intervals. However, if the patient has a “breakthrough” seizure, both peak and trough samples are recommended.
Procainamide Indications • Although not routine, procainamide could be monitored in patients responding inadequately to long-term control of cardiac arrhythmias. NOTE: Efficacy of procainamide in people reflects an active metabolite that is minimally formed in dogs. Recommended concentrations reflect both procainamide and its acetylated metabolite. Sample Collection • Because the halflife of procainamide is sufficiently short and the potential of adverse drug interactions sufficiently great, both peak and trough
405
Therapeutic Drug Monitoring
samples should be collected (see Table 18-1). A single trough sample can also be used to verify efficacy.
Theophylline Indications • In patients receiving the drug as a bronchodilator that have not experienced sufficient response and those suspected of reacting adversely to theophylline. Sample Collection • The half-life of regular theophylline is short enough that it is best to collect both peak and trough samples (see Table 18-1). For efficacy, a single trough sample is acceptable. For safety (i.e., detection of adverse reactions), a single peak sample can be collected. For slow-release preparations, absorption is slow enough that a single trough sample is sufficient. Dosing Modification • The dose of theophylline can be changed proportionately. Intervals can be modified if both peak and trough data are available.
Thyroid Hormones Indications • In any animal receiving thyroid supplementation (usually dogs) or animals with hyperthyroidism that are being medically managed (usually cats). Because thyroxine (T4) is the circulating hormone of interest (T3 being located primarily intracellularly), it is generally the hormone measured.
The majority of the hormone is bound to proteins and thus is pharmacologically inactive; therefore, free T4 (fT4) may be the preferred hormone to be tested. Equilibrium dialysis is the most accurate method to measure fT4. Sample Collection • Although concentrations of hormones may achieve steady state rapidly, the body may not equilibrate immediately. Physiologic equilibrium to the thyroid hormones may take 4 to 6 weeks, and monitoring should not take place until equilibrium is likely to have occurred (see Table 18-1). Likewise, response to drugs intended to control hyperthyroidism may take 3 to 4 weeks. Analysis • Methods that have been validated in the species of interest are preferred. Dosing Modification • Doses should be altered proportionately.
References Neff-Davis CA: Therapeutic drug monitoring in veterinary medicine, Vet Clin North Am Small Anim Pract 18(6): 1287, 1988. Pippenger CF, Massoud N: Therapeutic drug monitoring. In Benet LZ et al, editors: Pharmacokinetic basis for drug therapy, New York, 1984, Raven Press. Price CP: Analytical techniques for therapeutic drug monitoring, Clin Biochem 17:52, 1984. Therapeutic drug monitoring, clinical guide, Abbott Laboratories, Diagnostic Division, Dallas, TX, 1984, Abbott Laboratories. Wilson RC: Therapeutic drug monitoring, Auburn Vet 42(3):20, 1987.